5-substituted benzophenone hydrazone compounds and process for the production thereof

ABSTRACT

5-SUBSTITUTED BENZOPHENONE HYDRAZONES WHICH POSSESS AN ACTIVITY ON THE CENTRAL NERVOUS SYSTEM ARE DISCLOSED. THE 5-SUBSTITUTED BENZOPHENONE HYDRAZONES ARE PREPARED BY THE REACTION OF 5-SUBSTITUTED BENZOPHENONES WITH HYDRAZINE.

United States Patent Office 3,796,754 Patented Mar. 12, 1974S-SUBSTITUTED BENZOPHENONE HYDRAZONE COMPOUNDS AND PROCESS FOR THE PRO-DUCTION THEREOF Minoru Shindo, Tokyo, Morio Kakimoto, Yono, and HiroyukiNagano, Ageo, Japan, assignors to Chugai Seiyaku Kabushiki Kaisha,Tokyo, Japan N Drawing. Filed Apr. 10, 1972, Ser. No. 242,825 Claimspriority, application Japan, Apr. 8, 1971, 46/21,427; Mar. 23, 1972,47/223,555 Int. Cl. C07c 109/16 US. Cl. 260-566 B 3 Claims ABSTRACT OFTHE DISCLOSURE S-substituted benzophenone hydrazones which possess anactivity on the central nervous system are disclosed. The 5-substitutedbenzophenone hydrazones are prepared by the reaction of 5-substitutedbenzophenones with hydrazine.

This invention relates, in one aspect, to S-substituted benzophenonehydrazones of the general formula:

(wherein X is selected from the class consisting of nitro, hydroxyl,bromine and fluorine; R is selected from the class consisting ofhydrogen and alkyl) and, in another aspect, to a process for producingS-substituted benzophenone hydrazones.

The compounds represented by the above General Formula I are invariablynovel compounds and, as demonstrated by various animal experiments, havesuperior and different CNS activities in comparison with theconventional CNS drugs, for example benzodiazepine derivatives.Furthermore, those beneficial activities are such that they have beenlittle or not at all known in connection with the conventionalbenzodiazepine compounds. Thus, the compounds obtainable by the processof this invention are promising in that they might lead to thedevelopment of new, excellent CNS drugs.

The compounds represented by the Formula I have a neurotropic activity.Particularly, they act to depress the central nervous system and,therefore, are useful as sedative, tranquilizer, antidepressantantispastic and analgesic compounds. Depressive effect on the centralnervous system of the compounds can be determined according to themethod disclosed by W. L. Kuhn et al. Journal of Pharmacology andExperimental Therapeutics, 134, 60 (1961), wherein the degree ofdepression is determined by observing the sleeping time in miceprolonged by the oral administration of these compounds followed byintraperitoneal injection of soluble hexobarbital (sodium salt ofhexobarbital).

Analgesic activity of the compounds was determined either by theElectro-Stimulation Method of J. H. Burn et a1. BiologicalStandardization Oxford University Press (1950), wherein these compoundsare orally administered to mice followed by subjecting to electricstimulation, and counting the number of times stimulation is effecteduntil the mice squeak, or by Acetic Acid Writhing Method according to R.Koster et al., Federation Proceedings, 18, 412 (1969), wherein thecompounds are orally administered to mice, then acetic acid isintraperitoneally injected into the mice and the decrease in depressionof writhing of the mice caused by the intraperitoneal injection ofacetic acid is observed.

Toxicity is measured by the oral administration of the compounds to micefollowed by measuring a lethal dose which is indicated by LD The resultsexhibit that all the compounds represented by the Formula I areeffective. Some of the compounds are especially eflective in prolongingcentral nervous system depression time (sleeping time); the depressiontime is 3 times that of the control,'when they are administered in thelevel of 5 to 20 mg./kg. With respect to analgesic action, some of thecompounds were found to have more than 1.5 times the depression ratio incomparison with the control group by the Electro-Stimulation Method asdetermined 45 to minutes after administration of mg./kg. On the otherhand, more than 30% of depression ratio is observed according to theAcetic Acid Writhing Method.

Acute toxicity is observed with doses of 300 to 600 mg./ kg. 50)-Further, the biological activity of these hydrazones differs from thatof benzodiazepine derivatives such as Diazepam. When 5-25 mg./kg. of thehydrazones is administered to mice to which 0.1 mg./head of Reserpin hasbeen previously administered, the hypothermal activity of the mice isinhibited and the hydrazones exhibit effectiveness similar to the effecton biological activities eifected by imipraine, one of theantidepressants.

The compounds represented by the Formula I may be administered orallyintravenously or subcutaneously, if necessary, in the form of organic orinorganic acid addition salts. Though therapeutic dosage level of thecompounds may be varied depending upon specific activity of thecompounds and specific requirement, the dosage level is usually from 1to 100 mg./kg. per each administration to a warm blooded animal. Thecompounds of this invention may be administered in the form of isotonicsolution, elixir, suspension, capsule, tablet or powder which may beprepared by incorporating the compounds into usual solid or liquidcarriers or excipients according to the conventional pharmaceuticalpractice.

The compounds represented by the above General Formula I can be producedby reacting a 5-substituted benzophenone of the general formula:

wherein X is selected from the class consisting of nitro, hydroxyl,bromine and fluorine; R is selected from the class consisting ofhydrogen and alkyl, with hydrazine.

The hydrazine to be reacted with a S-substituted benzophenone of GeneralFormula II may be either anhydrous hydrazine or hydrazine hydrate.Compounds of'General Formula I can be obtained in particularly goodyields when anhydrous hydrazine and said 5-substituted benzop'henone(II) are refluxed in anhydrous alcohol. In this case, the reaction canbe carried to completion in a relatively short time if the reaction isconducted under pressure in a sealed tube or autoclave. When hydrazinehydrate is employed, the desired product can be obtained merely byrefluxing the reactants in a solvent in the presence of an acid. Theacid may be a mineral acid, such as hydrochloric acid or sulfuric acid,or an organic acid, such as acetic acid, although hydrochloric acid isthe most desirable. The acid is preferably used in an amount such thatthe mixture of the reactants and the acid prior to the reaction will bealkaline. The solvent may be a low-boiling alcohol such as methanol orethanol and need not be anhydrous.

The desired compounds can also be produced by the following methods,although these methods may not be more advantageous than those describedabove. Thus, one method may comprise heating a S-substitutedbenzophenone compound of General Formula II and hydrazine hydratetogether is a sealed tubular reaction at a high temperature; anothermethod may comprise refluxing the reactants in a comparativelyhigh-boiling solvent, e.g. diethylene glycol or n-butanol, for anadequate time; in still another method, one may reflux the reactants inethanol while continuously removing water from the reaction system usinga Soxhlet extractor.

Separation of the desired compound from the reaction mixture can beeasily effected by a conventional procedure, e.g. crystallization bycooling or extraction with an organic solvent such as chloroform.

The desired compound can also be isolated in the form of an acid salt,e.g. the salt of picric acid or hydrochloric acid. If required, thecompound can be purified by column chromatography on silica gel. Whilethe proportion of hydrazine should be at least equimolar relative to theS-substituted benzophenone, it is often advantageous to employ 40 to 100moles of hydrazine per mole of the benzophenone.

The following examples are further illustrative of the process of thisinvention.

EXAMPLE 1 To 50 g. (0.181 mole) of 2-amino-5-bromobenzophenone is added200 ml. of ethanol, followed by the addition of 200 m1. of ethanolsaturated with hydrogen chloride. Then 400 g. of 100% hydrazine hydrateis added, further followed by the addition of 800 m1. ethanol. Understirring, the mixture is refluxed for 7-8 hours. After the reaction hasbeen completed, the reaction mix ture is cooled to room temperature andchloroform is added. After washing with water, the extract is dried oversodium sulfate and concentrated under reduced pressure. Finally, etheris added to the concentrate, whereupon 2-amino-5-bromobenzophenonehydrazone is obtained as white crystals. The crystals are recovered byfiltration and recrystallized from ether. The procedure gives crystalsmelting at 161162 C.

Elementary analysis.-Calcd. for C H BrN (percent): C, 53.81; H, 4.17; N,14.48. Found (percent): C, 53.52; H, 3.96; N, 14.10.

EXAMPLE 2 To 50 g. (0.1723 mole) of 2-methylamino-5-bromobenzophenone isadded 200 ml. of ethanol, followed by the addition of 200 ml. of ethanolsaturated with hydrogen chloride. Then, 500 g. of 100% hydrazine hydrateand an additional 800 ml. of ethanol are added. With stirring, themixture is refluxed for 7-8 hours. After the reaction has been wmpleted,the mixture is cooled to room temperature and extracted with chloroform.The chloroform layer is washed with water, dried over sodium sulfate andconcentrated under reduced pressure. Finally, ether is added to the oilyresidue, which is then allowed to stand at room temperature, whereuponcolorless crystals of 2-methylamino-5-bromobenzophenone hydrazone areobtained. Recrystallization from chloroformn-hexane gives crystalsmelting at 64-66 C.

Elementary analysis.Calcd. for C H BrN (percent): C, 55.28; H, 4.64; N,13.81. Found (percent): C, 55.44; H, 4.76; N, 12.62.

EXAMPLE 3 To 30 g. (0.1308 mole) of 2-amino-5-fluorobenzophenone isadded 120 ml. of ethanol, followed by the addition of ml. ethanolsaturated with hydrogen chloride and, then, 230 g. of hydrazine hydrate.Then, 350 m1. of ethanol is added. Under stirring, the mixture isrefluxed for 6 hours. After the reaction has been completed, the mixtureis allowed to cool to room temper-, ature and shaken together withchloroform. The chloroform layer is separated, washed with 3 portions ofwater, dried over sodium sulfate and concentrated under reducedpressure. Finally, ether is added to the concentrate, whereupon2-amino-5-fluorobenzophenone hydrazone is obtained as white crystals.The crystals are recovered by filtration and recrystallized fromchloroformn-hexane. The procedure yields white needles melting at115.5-117.0 C.

Elementary analysis.'Ca1cd. for C H 'FN (percent): C, 68.11; H, 5.28; N,18.33. Found (percent): C, 68.06; H, 5.12; N, 18.29.

EXAMPLE 4 To 15 g. (0.065 mole) of 2-methylamino-5-fluorobenzophenone isadded 100 ml. of ethanol, followed by the addition of 60 ml. of ethanolsaturated with hydrogen chloride and, then, g. of 100% hydrazinehydrate. Then, 200 ml. of ethanol is further added. Under stirring, themixture is refluxed for 7-8 hours. After the reaction has beencompleted, the mixture is allowed to cool to room temperature and shakentogether with chloroform. The chloroform layer is separated, washed with3 potions of water, dried over sodium sulfate and concentrated underreduced pressure. The concentrate is columnchro-matographed (solventsystems: benzene and benzene-ether=1 1 The eluate is collected andconcentrated, followed by the addition of a mixture of ether andn-hexane. The mixture is allowed to stand overnight under cooling. Theprocedure yields pale yellowish crystals of 2-methylamino-5-fluorobenzophenone hydrazone. M.P. 7778 C. (after recrystallizationfrom ether-n-hexane).

Elementary analysis.Calcd. for C H FN (percent): C, 69.12; 1H, 5.80; N,17.27. Found (percent): C, 69.23;H, 5.78; N, 17.25.

EXAMPLE 5 To 6.7 g. (0.0295 mole) of 2-amino-5-hydroxybenzophenone isadded 30 ml. of ethanol saturated with hydrogen chloride, followed bythe addition of 60 g. of 100% hydrazine hydrate. Then, 200 ml. ofethanol is added. The mixture is refluxed under stirring for 5 hours.After the reaction has been completed, the reaction mixture is allowedto cool to room temperature and extracted with ether. The etheric layeris washed with water, dried over sodium sulfate and concentrated underreduced pressure. The oily concentrate is column-chromatographed(solvent system; benzenechloroform-ether:1:1:1). The eluate is collectedand concentrated under reduced pressure, followed by the addition ofether-n-hexane, whereupon 2-amino-5-hydroxybenzophenone hydrazone isobtained as yellow crystals. Recrystallization from ether-nhexane givescrystals melting at 121l22 C.

Elementary analysis.-Calcd. for C H N O (percent): C, 68.70; H, 5.77; N,18.49. Found (percent): C, 68.40; H, 5.52; N, 18.15.

EXAMPLE 6 To 10 g (0.0413 mole) of 2-amino-5-nitrobenzophenone is added50 ml. of ethanol, followed by the addition of 40 ml. ethanol-hydrogenchloride. Then, 150 g. of 100% hydrazine hydrate is added. At thismoment, the mixture is basic due to the pressure of hydrazine. Them, 250ml. of ethanol is added and the mixture is refluxed under stirring for5-7 hours, whereupon the reaction mixture becomes deep brown. After thereaction has been completed, the reaction mixture is allowed to cool toroom temperature and extracted with chloroform.

After washing with 3 portions of water, the chloroform layer isseparated, dried over sodium sulfate and concentrated under reducedpressure. Finally, ether is added to the residue, whereuponZ-amino-5-nitrobenzophenone hydrazone is obtained as yellowish browncrystals. The crystals are recovered by filtration and recrystallizedfrom chloroform-ether-n-hexane. M.P. 183 C.

Elementary analysis.-Calcd. for C H N O (percent): C, 60.93; H, 4.72; N,21.86. Found (percent): C,

The etheric mother fluid remaining after the recovery of crystals isallowed to stand at room temperature overnight, whereupon orange-coloredcrystals separate out. Recrystallization gives crystals melting at154-155 C. This product is an isomer of the 2-amino-5-nitrobenzophenonehydrazone obtained above.

Elementary analysis.-Calcd. for C H N O (percent): C, 60.93; H, 4.72; N,21.86. Found (percent): C, 60.61; H, 4.62; N, 21.59.

EXAMPLE 7 To g. (0.0396 mole) of 2-methylamino-5-nitrobenzophenone isadded 50 ml. of ethanol, followed by the addition of 45 ml.ethanol-hydrogen chloride. Then, 100 g. of 100% hydrazine hydrate isadded. At this moment, the mixture is hydrazine-basic. Then, 150 ml. ofethanol is added and the mixture is refluxed under stirring for 5-7hours, whereupon the reaction mixture becomes red in color. After thereaction has been completed, the reaction mixture is cooled to roomtemperature and chloroform is added. After washing with 3 portions ofwater, the chloroform layer is separated, dried over sodium sulfate andconcentrated under reduced pressure. Finally, ether is added to theconcentrate, whereupon 2-methylamino-5-nitrobenzophenone hydrozone isobtained as yellow needles. The crystals are recovered by filtration andrecrystallized from chloroform-ether. M.P. 175-176 C.

Elementary analysis.-Calcd. for C H N O (percent): C, 62.21; H, 5.22; N,20.73. Found (percent): C, 61.96; H, 5.31; N, 20.49.

The etheric mother fluid after the recovery of crystals wherein R is amember of the group consisting of a hydrogen atom and a methyl radical.

2. 2-amino-5-nitrobenzophenone hydrazone in accordance with claim 1.

3. 2-methylamino-5-nitrobenzophenone hydrazone in accordance with claim1.

References Cited Sulkowski et al.: Medicinal Chem., vol. 7, p. 386(1964).

Degering: An Outline of Organic Nitrogen Compounds, p. 384 (1950).

Chem. Abstr., vol. 57, column 9856(h) (1962).

BERNARD HELFIN, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US.Cl. X.R. 424327

